End-stage renal disease (ESRD) is a late-onset multi-factorial disease that primarily occurs in a small subset of patients with diabetes mellitus, hypertension or chronic glomerulonephritis. ESRD incidence is rising with an annual mortality of about 20% in incident cases. ESRD clusters in families and familial aggregation is a more powerful predictor of whether an individual with diabetes mellitus, hypertension or chronic glomerulonephritis will develop ESRD. However, no particular genetic mechanism responsible for the renal function damage that ultimately leads to ESRD has yet been identified. We will recruit 150 affected relative pairs concordant for ESRD, and 100 relative pairs discordant for ESRD (but concordant for diabetes mellitus or hypertension) from 12 hemodialysis centers, 2 peritoneal dialysis centers and 1 transplant center as part of a study to identify genetic risk factors for ESRD. We will collect extensive family history and medical history, as related to ESRD, on all members of the family recruited into the study. Blood will be obtained from all consenting family members. DNA will be extracted from lymphocytes and candidate genes and other markers will be genotyped. A least half the candidate genes/regions being examined are novel candidates and have not been evaluated for linkage with ESRD before. These include the receptors for the growth factors and the human regions syntenic to ESRD-related loci in rat or mouse models of ESRD. Data will be analyzed using model-free linkage analysis. This data-set is expected to be complex and we have to sub-divide the data, by diagnosis, for analysis. We anticipate that this study will lead to identification of gene(s) for ESRD. This application is intended to provide a core for further, ore extensive acquisition of ESRD phenotype and genotype data. We intended to expand the entire project to include a genome scan and have designed subject collection to accommodate this goal.